Encuesta para determinar la situación actual de la E.I.A

As described above SCORE was the first attempt to provide risk estimates for multiple countries. However, it is applicable only to Europe, period effects have substantially weakened the models’ utility, and they probably did not account sufficiently for heterogeneity in CVD rates across Europe.

A second attempt was made by the WHO in its guidelines on the assessment and management of CVD risk.(197) This was the first time that a global approach was taken, to provide an approximate risk model

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for countries with limited prospect of deriving their own models. The project can be further congratulated on a further conceptual innovation: instead of taking the risk factor Hazard Ratios from the same dataset where the estimate of baseline risk is taken from, it was perhaps the first CVD model to draw these inferences from separate sources.

However, the application of this idea had substantial limitations. The baseline disease risk was taken from an early iteration of the Global

Burden of Disease Study that had not been peer reviewed. The underlying data quality of this has been subject to much criticism. The WHO risk developers compounded this limitation by opting to predict not just fatal CVD, but also nonfatal CVD whose international data quality is extremely heterogeneous. Secondly, the risk factor Hazard Ratios (HR) were taken not from a single joint regression that involved all risk factors, but

apparently some HRs were estimated from univariate models that had only been adjusted for age and sex.(198) This can lead to large errors in overestimating risk for persons with more than one risk factor, and subsequent problems with discrimination and calibration. As such, the WHO model has never been published in a peer-reviewed form and will be discarded in the rest of this thesis.

A third attempt was made in 2015 with the derivation of GLOBORISK, initially for 11 countries (198) which was later extended to 182

countries(199). Their second publication was published in March 2017, by which point I had completed most of the analyses later presented in this thesis. Therefore, this publication could be viewed as a parallel

development to my own work.

The GLOBORISK project should be congratulated for continuing the vision of the earlier WHO model, but managing to translate this into a reliable model that could contend as the default option for most countries of the world. However, the GLOBORISK model contains two considerable limitations, the first around calibration and the second around discrimination.

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In contrast to SCORE, GLOBORISK added nonfatal events to its outcome. This can be seen as a strength in terms of trying to bring the rest of the world to a state comparable to Western Europe and the North America, in terms of studies of interventions, guidelines and national programmes. However, adding nonfatal events also weakens the model, by introducing substantial inter-country heterogeneity in data quality. This may be the reason why the GLOBORISK website

(http://www.globorisk.org) predicts higher risk of fatal/nonfatal CVD for male participants in Finland, when compared to risk estimates for

equivalent participants from Estonia, Poland and the Czech Republic. This is inconsistent with the epidemiology of this region, as demonstrated in figure 12.

Figure 12. Comparison of the burden of ischaemic cardiovascular disease across four European countries.

The data describe the Disability-adjusted Life Year (DALY) burden for men of all ages in 2016. Data are from (200). This geographical pattern is not capitulated in the GLOBORISK CVD risk prediction model.

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A second explanation for these implausible predictions is how the GLOBORISK predicts risk for the year 2024, using linear extrapolation from trends between 2001-2015. Trends in Eastern Europe have been chaotic, and there is little evidence to suggest that these extrapolations will hold true. Finally, although the GLOBORISK project set out with a focus on improving calibration, no calibration data are presented in either paper nor its appendices, other than the largely discredited Hosmer- Lemeshow χ² test. To summarize this first limitation, I would have found the GLOBORISK project much more useful, had it focused exclusively on predicting fatal CVD events, and had it demonstrated calibration.

As a second limitation, the authors assumed that the HRs found in the USA are generalizable to the other 181 countries. There is very little prospective cohort data to empirically test this claim. The authors cited one analysis, where HRs from Australia/New Zealand were compared against “Asia”. Small differences were found for some HRs (such as blood pressure and cholesterol).(201) However, this study amalgamated data from primarily China and Japan into one large region, despite the fact that these two countries have very different profiles of economic development and CVD. The GLOBORISK team secondly cite the INTERHEART study as evidence for the homogeneity of Odds Ratios between regions. This study explored the range of Odds Ratios for 6 risk factors, across 11 regions (i.e. 60 comparison groups). Across all 6 risk factors, there appeared to be considerable evidence that heterogeneous Odds Ratios were unlikely to arise from chance alone (figure 13).

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Figure 13. Regional variation in Odds Ratios for six risk factors for acute myocardial infarction, from the INTERHEART study.

Confidence intervals are 99%, while 95% confidence intervals will be narrower. Adapted from (202), where I have purposefully selected those regions with the greatest heterogeneity.

However, the INTERHEART authors did not explore this observation statistically, for example no significance tests nor Bonferroni corrections are reported. It is also possible that the decision to present 99%

Confidence Intervals, as opposed to the established practice of 95% Confidence Intervals, may have been with the intent of projecting an illusion of homogeneity to those who were unaware of this detail.

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Therefore to summarize, at current there are no reliable analyses from which to infer whether it is appropriate or not to extend Hazard Ratios and other risk factor coefficients from Western European/North American studies onto other regions of the world. The answer to this question

informs the design of risk prediction models elsewhere, but also estimates of global burden of disease, and priority setting for national public health authorities.